Question

what is the link of ketone mteabolism with other metabolism

Answer 1

The term “ketogenesis” defines a series of reactions that leads to the formation of so-called ketone bodies, which include β-hydroxybutyrate (bHB), acetoacetate and acetone. The process is primarily carried out in the mitochondria of hepatocytes, but kidney epithelia, astrocytes and enterocytes are also capable of, albeit to a lesser extent, producing ketone bodies. Ketogenesis requires efficient mitochondrial β-oxidation of fatty acids. Medium chain fatty acids, such as octanoate freely enter
mitochondria and are readily broken down to acetyl-CoA. However, long chain fatty acids, such as palmitate require carnitine-mediated transport to mitochondria through carnitine palmitoyltransferase activity is regulated by the concentration of malonyl-CoA, an initial intermediate of fattyacid synthesis; therefore, CPT1 serves a regulatory node between fatty acid oxidation andb biosynthesis Fatty acid oxidation product, acetyl-CoA is the substrate for ketogenesis and the first step involves condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA in the reaction catalyzed by acetoacetyl-CoA thiolase . Next, the third acetyl-CoA molecule is attached to form 3-hydroxy-3-methylglytaryl-CoA (HMG-CoA) by HMGCS2 which is the rate-limiting enzyme of the whole pathway. HMG-CoA is then transformed into the first type of ketone body, acetoacetate, and acetyl-CoA by HMG-CoA lyas. The majority of newly formed acetoacetate is then reduced to bHB by NADH-dependent β-hydroxybutyrate dehydrogenase β-hydroxybutyrate is the most abundant ketone body in the circulation. The remaining fraction of acetoacetate in some tissues (such as lungs) is spontaneously decarboxylated into volatile acetone, the simplest ketone body.In fact, the presence of acetone in the air exhaled by diabetic patients is a symptom of a life threatening

condition known as ketoacidosis.The acetyl CoA formed in fatty acid oxidation enters the citric acid cycle only if fat and carbohydrate degradation are appropriately balanced. Acetyl
lCoA must combine with oxaloacetate to gain entry to the citric acid cycle. The availability of oxaloacetate, however, depends on an adequate supply of carbohydrate. Recall that oxaloacetate is normally formed from pyruvate, the product of glucose degradation in glycolysis. If carbohydrate is unavailable or improperly utilized, the concentration of oxaloacetate is lowered and acetyl CoA cannot enter the citric acid cycle. This dependency is the molecular basis of the adage that fats burn in the flame of carbohydrates. In fasting or diabetes, oxaloacetate is consumed to form glucose by the gluconeogenic pathway and hence is unavailable for condensation with acetyl CoA. Under these conditions, acetyl CoA is diverted to the formation of acetoacetate and D-3-hydroxybutyrate. Acetoacetate, D-3-hydroxybutyrate, and acetone are often referred to as ketone bodies.Abnormally high levels of ketone bodies are present in the blood of untreated diabetics. Acetoacetate is formed from acetyl CoA in three steps . Two molecules of acetyl CoA condense to form acetoacetyl CoA. This reaction, which is catalyzed by thiolase, is the reverse of the thiolysis step in the
oxidation of fatty acids. Acetoacetyl CoA then reacts with acetyl CoA and water to give3-hydroxy 3-methylglutaryl CoA (HMG-CoA) and CoA. This condensation resembles the one catalyzed by citrate synthasj. This reaction, which has a favorable equilibrium owing to the hydrolysis of a thioester linkage, compensates for the unfavorable equilibrium in the formation of acetoacetyl CoA. 3-Hydroxy-3-methylglutaryl CoA is then cleaved to acetyl CoA and acetoacetate. The sum of these reactions is
2 Acetyl CoA 1 H2O ¡acetoacetate 1 2 CoA 1 H1
D-3-Hydroxybutyrate is formed by the reduction of acetoacetate in the mitochondrial matrix by D-3-hydroxybutyrate dehydrogenase. The ratio of hydroxybutyrate to acetoacetate depends on the NADH/NAD1 ratio inside mitochondria.
Because it is a b-ketoacid, acetoacetate also undergoes a slow, spontaneous decarboxylation to acetone. The odor of acetone may be detected in the breath of a person who has a high level of acetoacetate in the blood.Ketone bodies are a major fuel in some tissues.The major site of the production of acetoacetate and 3-hydroxybutyrate is the liver. These substances diffuse from the liver mitochondria into the blood and are transported to other tissues such as heart and kidney . Acetoacetate and 3-hydroxybutyrate are normal fuels of respiration and are quantitatively important as sources of energy. Indeed, heart muscle and the renal cortex use acetoacetate in preference to glucose. In contrast, glucose is the major fuel for the brain and red blood cells in well-nourished people on a balanced diet. However, the brain adapts to the utilization of acetoacetate during starvation and diabetes. In prolonged starvation, 75% of the fuel needs of the brain are met by ketone bodies. Acetoacetate is converted into acetyl CoA in two steps. First, acetoaceltate is activated by the transfer of CoA from succinyl CoA in a reaction catalyzed by a specific CoA transferase. Second, acetoacetyl CoA is cleaved by thiolase to yield two molecules of acetyl CoA, which can then enter citric acid cycle (Fikk). The liver has acetoacetate available to supply to other organs because it lacks this particular CoA transferase. 3-Hydroxybutyrate requires an additional step to yield acetyl CoA. It is first oxidized to produce acetoacetate, which is processed as heretofore described, and NADH for use in oxidative phosphorylation.
Animals cannot convert fatty acids into glucose:
A typical human being has far greater fat stores than glycogen stores. However, glycogen is necessary to fuel very active muscle, as well as the brain, which normally uses only glucose as a fuel. When glycogen stores are low, why can’t the body make use of fat stores and convert fatty acids into glucose? Because animals are unable to effect the net synthesis of glucose from fatty acids. Specifically, acetyl CoA cannot be converted into pyruvate or oxaloacetate in animals. Recall that the reaction that generates acetyl CoA from pyruvate is irreversible. The two carbon atoms of the acetyl group of acetyl CoA enter the citric acid cycle, but two carbon atoms leave the cycle in the decarboxylations catalyzed by isocitrate dehydrogenase and a-ketoglutarate dehydrogenase. Consequently, oxaloacetate is regenerated, but it is not formed de novo when the acetyl unit of acetyl CoA is oxidized by the citric acid cycle. In essence, two carbon atoms enter the cycle as an acetyl group, but two carbons leave the cycle as CO2 before oxaloacetate is generated. Consequently, no net synthesis of oxaloacetate is possible. In contrast, plants have two additional enzymes enabling them to convert the carbon atoms of acetyl CoA into oxaloacetate. Acetoacetate and 3-hydroxybutyrate are short-chain (4-carbon) organic acids that can freely diffuse across cell membranes. Therefore, ketone bodies can serve as a source of energy for the brain (which does not utilize fatty acids) and the other peripheral organs mentioned above. Ketone bodies are filtered and reabsorbed in the kidney. At physiologic pH, these organic acids dissociate completely. The large hydrogen-ion load generated during their pathologic production, in diabetic ketoacidosis, for example, rapidly overwhelms the normal buffering capacity and leads to a metabolic acidosis with an increased anion gap.Insulin inhibits lipolysis and ketogenesis and stimulates lipogenesis by triggering the inhibitory dephosphorylation of hormone-sensitive lipaseand the activating dephosphorylation of acetyl CoA carboxylase. In the adipocytes, dephosphorylation of hormone-sensitive lipaseinhibits the breakdown of triglycerides to fatty acids and glycerol, the rate-limiting step in the release of free fatty acids (lipolysis) from the adipocyte.Glucagon stimulates ketogenesis by doing the opposite of insulin. Glucagon triggers the phosphorylation of both hormone-sensitive lipaseand acetyl CoA carboxylase by cyclic AMP-dependent protein kinase. In the adipocytes, phosphorylation of hormone-sensitive lipase by cyclic AMP-dependent protein kinase stimulates the release of fatty acids from triglycerides.Free fatty acids are released into the circulation by lipolysis and broken down into multiple copies of acetyl CoA by β-oxidation. Under conditions of low glucose availability ketogenesis occurs in the liver producing the three ketone bodies, 3-hydroxybutyrate, acetoacetate and acetone. The production of the first two is catalysed by four enzymes: acetoacetyl CoA thiolase (denoted by 1), HMGCoA synthase (2), HMG CoA lyase (3) and 3hydroxy butyrate dehydrogenase (4). The acetone is formed by non-enzymic decarboxylation of acetoacetate and cannot be used as an energy source. Acetoacetate and 3-hydroxybutyrate pass from the liver to the general circulation and are absorbed by non-hepatic tissues where they can be used as fuel. The 3-hydroxybutyrate is oxidized to acetoacetate by 3 hydroxy butyrate dehydrogenase and then converted to acetoacetyl CoA by acetoacetyl succinyl CoA transferase (II). The acetoacetyl CoA is then split by acetoacetyl CoA thiolase (III) into two molecules of acetyl CoA which are metabolized into CO2 and H2O via the TCA cycle and oxidative phosphorylation generating many molecules of ATP.